Project #3. Approximately 10% of patients who successfully suppress HIV-1 in the blood with antiretroviral therapy have persistently higher levels of virus In the CSF. This likely represents ongoing replication in the CNS which has the potential to contribute to or worsen HIV-associated neurocognitive impairment. In Project 3 we will examine factors associated with the failure to suppress viral replication in the CNS. We will examine the virus present in the CSF to determine if it is T cell-tropic or macrophage-tropic. We will determine the drug levels in the CSF to determine if persistent replication could be the result of inadequate drug exposure in the CNS. A contributor to low drug levels that we will examine may be polymorphisms in drug transporter genes, which encode proteins that play a critical role In protecting the CNS from xenobiotics. We will also determine if persistent replication is associated with the development of drug resistance. Collectively, these studies will bring important insights to the significance and risks of persistent replication in the CNS in the face of otherwise successful therapeutic intervention.